Ethanolamine → Linagliptin

HRID 44901Notes

Reaction equation

HRID 44901 reaction equation
[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([N:34]5C(=O)C6=CC=CC=C6C5=O)[CH2:29]4)=[N:18][C:17]=3[N:16]([CH3:45])[C:14]2=[O:15])[N:3]=1.C(CN)O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([NH2:34])[CH2:29]4)=[N:18][C:17]=3[N:16]([CH3:45])[C:14]2=[O:15])[N:3]=1

Participants

4

Reactant 2

HCID 700EthanolamineHCID 595225287-(2-Butyn-1-yl)-8-[(3R)-3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-piperidinyl]-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione

Product 1

HCID 10096344Linagliptin

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
82.5 °C

Procedure

1800 kg (3 mol) of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-phthalimidopiperidin-1-yl)-xanthine are heated to 80-85° C. in 18 liters of toluene. Subsequently, 1.815 liters (30 mol) of ethanolamine are added to the suspension at 75-80° C. To complete the reaction, the mixture is stirred at 80-85° C. for 2 hours, in the course of which the solids go into solution. Subsequently, the phases are separated. The ethanolamine phase is washed twice with warm toluene (4 liters each time). The combined toluene phases are washed twice with 8 liters each time of water at 75-80° C. From the toluene phase, 22 liters of toluene are distilled off under reduced pressure. 4 liters of tert.-butyl methyl ether are metered at 40-50° C. to the resulting suspension and subsequently cooled to 0-5° C. The product is isolated by filtration, washed with tert.-butyl methyl ether and suction-dried. The moist crude substance is subsequently heated to reflux with 5 times the amount of absolute ethanol and the hot solution is clarified by filtration through activated carbon. After the filtrate has been cooled to 20° C. and crystallization has set in, it is diluted to double the volume with tert.-butyl methyl ether. The suspension is cooled to 2° C., stirred for a further 2 hours, filtered with suction and dried at 45° C. in a vacuum drying cabinet.

Workup

  1. customthe reaction
  2. customSubsequently, the phases are separated
  3. washThe ethanolamine phase is washed twice with warm toluene (4 liters each time)
  4. washThe combined toluene phases are washed twice with 8 liters each time of water at 75-80° C
  5. distillationFrom the toluene phase, 22 liters of toluene are distilled off under reduced pressure
  6. customare metered at 40-50° C. to the resulting suspension
  7. temperaturesubsequently cooled to 0-5° C
  8. customThe product is isolated by filtration
  9. washwashed with tert.-butyl methyl ether
  10. customsuction-dried
  11. temperatureThe moist crude substance is subsequently heated
  12. temperatureto reflux with 5 times the amount of absolute ethanol
  13. filtrationthe hot solution is clarified by filtration through activated carbon
  14. temperatureAfter the filtrate has been cooled to 20° C.
  15. customcrystallization
  16. additionis diluted
  17. temperatureThe suspension is cooled to 2° C.
  18. stirringstirred for a further 2 hours
  19. filtrationfiltered with suction
  20. customdried at 45° C. in a vacuum
  21. customdrying cabinet

Sources & evidence

ORD record
ord-0ea11bd1f8224e8592d04ed8dcf07db0
Source dataset
uspto-grants-2013_09
Patent number
US08541450B2

Reaction notes

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